PNAS Plus Significance Statements

Phase transitions in semidefinite relaxations

Adel Javanmard, Andrea Montanari, and Federico Ricci-Tersenghi

Modern data analysis requires solving hard optimization problems with a large number of parameters and a large number of constraints. A successful approach is to replace these hard problems by surrogate problems that are convex and hence tractable. Semidefinite programming relaxations offer a powerful method to construct such relaxations. In many instances it was observed that a semidefinite relaxation becomes very accurate when the noise level in the data decreases below a certain threshold. We develop a new method to compute these noise thresholds (or phase transitions) using ideas from statistical physics. (See pp. E2218–E2223.)

Necessity of capillary modes in a minimal model of nanoscale hydrophobic solvation

Hydrophobic effects, which play a crucial role in many chemical and biological processes, originate in the statistics of microscopic density fluctuations in liquid water. Chandler has established the foundation for a simple and unified understanding of these effects, by identifying essential aspects of water’s intermolecular structure while accounting for its proximity to phase coexistence. Here, we show that coarse-grained models based on this perspective, when constructed to include the statistics of capillary waves at interfaces, can achieve remarkable agreement with results of atomistically detailed simulations. Highly efficient and lacking adjustable parameters, such models hold promise as powerful tools for studying multiscale problems in hydrophobic solvation. (See pp. E2224–E2230.)

Microfluidic organ-on-a-chip technology is poised to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Here we demonstrate a sensor-integrated platform permitting real-time tracking of the dynamics of metabolic adaptation to mitochondrial dysfunction. Our approach permits detection of chemical toxicity before any effects on cell or tissue viability can be observed. (See pp. E2231–E2240.)

Population size does not explain past changes in cultural complexity

Krist Vaesen, Mark Collard, Richard Cosgrove, and Wil Roebroeks

Archaeologists have long tried to understand why cultural complexity often changed in prehistory. Recently, a series of highly influential formal models have suggested that demography is the key factor. According to these models, the size of a population determines its ability to invent and maintain cultural traits. In this paper, we demonstrate that the models in question are flawed in two important respects: They use questionable assumptions, and their predictions are not supported by the available archaeological and ethnographic evidence. As a consequence, little confidence can be invested in the idea that demography explains the changes in cultural complexity that have been identified by archaeologists. An alternative explanation is required. (See pp. E2241–E2247.)

A neural link between affective understanding and interpersonal attraction

Humans interacting with other humans must be able to understand their interaction partner’s affect and motivations, often without words. We examined whether people are attracted to others whose affective behavior they can easily understand. For this, we asked participants to watch different persons experiencing different emotions. We found the better a participant thought they could understand another person’s emotion the more they felt attracted toward that person. Importantly, these individual changes in interpersonal attraction were predicted by activity in the participant’s reward circuit, which in turn signaled how well the participant’s “neural vocabulary” was suited to decode the other’s behavior. This research elucidates neurobiological processes that might play an important role in the formation and success of human social relations. (See pp. E2248–E2257.)

Corroles are macrocyclic molecules related to porphyrins that exhibit intense light absorptions in the visible region. They also are very bright emitters, with luminescence quantum yields over 50% in some cases. Importantly, we have discovered that two corroles functionalized with carboxylate groups at different ring locations exhibit anticancer activity superior to cisplatin. Although the synthetic route to direct carboxylation of the tetrapyrrolic framework requires the use of phosgene, installing aminocaproate on the fluorophenyl ring by nucleophilic aromatic substitution uses mild conditions with biocompatible reagents, requiring only simple purification and providing ready access to structurally complex corroles. Carboxylated corroles are very rapidly taken up by cells, with an order of magnitude gain in dark cytotoxicity likely owing to greater cell permeability. (See pp. E2258–E2266.)

Functional architecture of the Reb1-Ter complex of Schizosaccharomyces pombe

Transcription termination of rRNA genes by RNA polymerase I (pol I) in fission yeast requires the binding of the Reb1 protein to a terminator site (Ter). Termination is physiologically necessary because its elimination can cause replication–transcription collision and induction of genome instability. Furthermore, without termination, pol I can become unproductively sequestered on the DNA templates. We have determined the crystal structure of fission yeast terminator protein Reb1-Ter complex revealing its functional architecture. Structure-guided functional analysis revealed that it is not just tight binding of the protein to Ter but protein–protein interactions with the Rpa12 subunit of RNA polymerase I that causes transcriptional arrest. (See pp. E2267–E2276.)

Eubacterial protein synthesis entails formation of an unlocked preinitiation complex consisting of the 30S ribosomal subunit, initiation factors, mRNA, and initiator tRNA. A conformational change in the subunit accompanies mRNA–tRNA codon–anticodon base-pairing generating a locked 30S complex. If correctly formed, this complex associates with the 50S ribosomal subunit forming a 70S complex, and the initiation factors are ejected. We show that the translational inhibitor GE81112 targets this essential step, hampering formation of a canonical codon–anticodon interaction and stalling the 30S in an unlocked state. Moreover, in the presence of GE81112 three rRNA helices, h44/h45/h24a, are stabilized in a disengaged conformation, suggesting that their conformation is associated with tRNA/mRNA decoding and transition of the 30S from unlocked to locked state. (See pp. E2286–E2295.)

In this report we describe the generation of tissue-regenerative multipotent stem cells (iMS cells) by treating mature bone and fat cells transiently with a growth factor [platelet-derived growth factor–AB (PDGF-AB)] and 5-Azacytidine, a demethylating compound that is widely used in clinical practice. Unlike primary mesenchymal stem cells, which are used with little objective evidence in clinical practice to promote tissue repair, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner without forming tumors. This method can be applied to both mouse and human somatic cells to generate multipotent stem cells and has the potential to transform current approaches in regenerative medicine. (See pp. E2306–E2315.)

T cells generate their T-cell receptors (TCR) through somatic rearrangement of their underlying genomic V(D)J regions. Contrary to previous transgenic TCR models, our TCR models generated through somatic cell nuclear transfer are precise copies of the original T cell. Here, we developed a novel somatic cell nuclear transfer model of natural arising regulatory T (nTreg) cells. In our monoclonal model, we found a well-defined nTreg population in the thymus, contradicting previous reports that intraclonal competition and thymic niche are limiting factors in nTreg development. Moreover, we found a novel fate-determining role for the TCR β-chain in nTreg cells. Interestingly, we also discovered a novel T-cell subset that functions as peripheral precursor of nTreg cells. (See pp. E2316–E2325.)

The human endogenous retrovirus (HERV) group HERV-K contains nearly intact and insertionally polymorphic integrations among humans, many of which code for viral proteins. Expression of such HERV-K proviruses occurs in tissues associated with cancers and autoimmune diseases, and in HIV-infected individuals, suggesting possible pathogenic effects. Proper characterization of these elements necessitates the discrimination of individual HERV-K loci; such studies are hampered by our incomplete catalog of HERV-K insertions, motivating the identification of additional HERV-K copies in humans. By examining >2,500 sequenced genomes, we have discovered 19 previously unidentified HERV-K insertions, including an intact provirus without apparent substitutions that would alter viral function, only the second such provirus described. Our results provide a basis for future studies of HERV evolution and implication for disease. (See pp. E2326–E2334.)

The large-conductance, voltage-gated, calcium (Ca2+)-activated potassium channel (BKCa) plays an important role in regulating the membrane potential of uterine muscle cells. We demonstrate that BKCa interacts with the immunomodulator α-2-macroglobulin (α2M) and its receptor low-density lipoprotein receptor-related protein 1 in human uterine muscle cells isolated from pregnant women. Furthermore, we report that activated α2M regulates BKCa activity and that activated α2M and BKCa together control Ca2+ oscillations in the cells, a process dependent on store-operated Ca2+ entry. This study reveals a previously unidentified modulator of the BKCa channel and may imply a link between inflammatory processes and excitation changes in the uterine muscle during pregnancy. (See pp. E2335–E2344.)

Blood-sucking sand flies from disparate global regions have a predilection for feeding on the marijuana plant (Cannabis sativa), and the findings hint at a potential avenue for controlling sand flies, which can transmit leishmaniasis.